Considerations for Drug Interactions on QTc in Exploratory COVID-19 Treatment
Hydroxychloroquine and azithromycin have been touted for potential prophylaxis or treatment for coronavirus disease 2019 (COVID-19). Both drugs are listed as definite causes of torsade de pointes on crediblemeds.org. There are occasional case reports of hydroxychloroquine prolonging the QT interval and provoking torsade de pointes1–4 when used to treat systemic lupus erythematosus. Antimalarial prophylactic drugs, such as hydroxychloroquine, are believed to act on the entry and postentry stages of SARS-CoV (severe acute respiratory syndrome coronavirus) and SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection, likely through effects on endosomal pH and the resulting underglycosylation of angiotensin-converting enzyme 2 receptors that are required for viral entry.5
The widely used antibiotic azithromycin is increasingly recognized as a rare cause of QT prolongation,6,7 serious arrhythmias,8,9 and increased risk for sudden death10; advanced age and female sex have been implicated as risk factors. It is interesting that azithromycin also can provoke nonpause-dependent polymorphic ventricular tachycardia.11,12 The US Food and Drug Administration Perspective supported the observation that azithromycin administration leaves the patient vulnerable to QTc interval prolongation and torsade de pointes.13
Basic electrophysiologic studies suggest that both hydroxychloroquine and azithromycin can provoke proarrhythmia by mechanisms beyond blockage of IKr implicated in usual cases of torsade de pointes.14,15 The effect of the combination of these agents on QT or arrhythmia risk has not been studied. There are limited data evaluating the safety of combination therapy. Multiple randomized trials are currently being initiated.
Seriously ill patients often have comorbidities that can increase the risk of serious arrhythmias. These include hypokalemia, hypomagnesemia, fever,16 and an inflammatory state.17 Mechanisms to minimize arrhythmia risk include the following:
•
Electrocardiographic/QT interval monitoring
◦
Withhold the drugs in patients with baseline QT prolongation (eg, QTc ≥500 ms) or with known congenital long QT syndrome.
◦
Monitor cardiac rhythm and QT interval; withdraw the drugs if QTc exceeds a preset threshold of 500 ms.
◦
In critically ill patients with COVID-19, frequent caregiver contact may need to be minimized, so optimal electrocardiographic interval and rhythm monitoring may not be possible.
•
Correction of hypokalemia to >4 mEq/L and hypomagnesemia to >2 mg/dL
•
Avoidance of other QTc-prolonging agents5 whenever feasible
Safety considerations for use of hydroxychloroquine and azithromycin in clinical practice have been described.18
Some of the current drugs repurposed for COVID-19 treatment are listed in the Table.
| Possible COVID-19 Treatment | CredibleMeds.org Classification | VT/VF/TdP/LQTS in FAERS | Cardiac Arrest in FAERS |
|---|---|---|---|
| Repurposed antimalarial agents | |||
| Chloroquine | Known risk | 72 | 54 |
| Hydroxychloroquine | Known risk | 222 | 105 |
| Repurposed antiviral agent | |||
| Lopinavir/ritonavir | Possible risk | 27 | 48 |
| Adjunct agent | |||
| Azithromycin | Known risk | 396 | 251 |
COVID-19 indicates coronavirus disease 2019; FAERS, US Food and Drug Administration Adverse Event Reporting System; LQTS, long QT syndrome; TdP, torsade de pointes; VF; ventricular fibrillation; and VT, ventricular tachyarrhythmia. Modified from Giudicessi et al5 with permission from the publisher. Copyright © 2020 Mayo Foundation for Medical Education and Research.
References
1.
Chen CY, Wang FL, Lin CC. Chronic hydroxychloroquine use associated with QT prolongation and refractory ventricular arrhythmia. Clin Toxicol (Phila). 2006;44:173–175. doi: 10.1080/15563650500514558
2.
Morgan ND, Patel SV, Dvorkina O. Suspected hydroxychloroquine-associated QT-interval prolongation in a patient with systemic lupus erythematosus. J Clin Rheumatol. 2013;19:286–288. doi: 10.1097/RHU.0b013e31829d5e50
3.
O’Laughlin JP, Mehta PH, Wong BC. Life threatening severe QTc prolongation in patient with systemic lupus erythematosus due to hydroxychloroquine. Case Rep Cardiol. 2016;2016:4626279. doi: 10.1155/2016/4626279
4.
de Olano J, Howland MA, Su MK, Hoffman RS, Biary R. Toxicokinetics of hydroxychloroquine following a massive overdose. Am J Emerg Med. 2019;37:2264.e5–2264.e8. doi: 10.1016/j.ajem.2019.158387
5.
Giudicessi JR, Noseworthy PA, Friedman PA, Ackerman MJ. Urgent guidance for navigating and circumventing the QTc prolonging and torsadogenic potential of possible pharmacotherapies for COVID-19 [published online March 25, 2020]. Mayo Clin Proc. doi: 10.1016/j.mayocp.2020.03.024. https://www.elsevier.com/__data/assets/pdf_file/0004/996745/MCP_Possible-COVID-19-Pharmacotherapies.pdf
6.
Choi Y, Lim HS, Chung D, Choi JG, Yoon D. Risk evaluation of azithromycin-induced QT prolongation in real-world practice. Biomed Res Int. 2018;2018:1574806. doi: 10.1155/2018/1574806
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Sears SP, Getz TW, Austin CO, Palmer WC, Boyd EA, Stancampiano FF. Incidence of sustained ventricular tachycardia in patients with prolonged QTc after the administration of azithromycin: a retrospective study. Drugs Real World Outcomes. 2016;3:99–105. doi: 10.1007/s40801-016-0062-9
8.
Huang BH, Wu CH, Hsia CP, Yin Chen C. Azithromycin-induced torsade de pointes. Pacing Clin Electrophysiol. 2007;30:1579–1582. doi: 10.1111/j.1540-8159.2007.00912.x
9.
Kezerashvili A, Khattak H, Barsky A, Nazari R, Fisher JD. Azithromycin as a cause of QT-interval prolongation and torsade de pointes in the absence of other known precipitating factors. J Interv Card Electrophysiol. 2007;18:243–246. doi: 10.1007/s10840-007-9124-y
10.
Ray WA, Murray KT, Hall K, Arbogast PG, Stein CM. Azithromycin and the risk of cardiovascular death. N Engl J Med. 2012;366:1881–1890. doi: 10.1056/NEJMoa1003833
11.
Kim MH, Berkowitz C, Trohman RG. Polymorphic ventricular tachycardia with a normal QT interval following azithromycin. Pacing Clin Electrophysiol. 2005;28:1221–1222. doi: 10.1111/j.1540-8159.2005.50146.x
12.
Yang Z, Prinsen JK, Bersell KR, Shen W, Yermalitskaya L, Sidorova T, Luis PB, Hall L, Zhang W, Du L, et al. Azithromycin causes a novel proarrhythmic syndrome. Circ Arrhythm Electrophysiol. 2017;10:e003560. doi: 10.1161/CIRCEP.115.003560
13.
Mosholder AD, Mathew J, Alexander JJ, Smith H, Nambiar S. Cardiovascular risks with azithromycin and other antibacterial drugs. N Engl J Med. 2013;368:1665–1668. doi: 10.1056/NEJMp1302726
14.
Zhang M, Xie M, Li S, Gao Y, Xue S, Huang H, Chen K, Liu F, Chen L. Electrophysiologic studies on the risks and potential mechanism underlying the proarrhythmic nature of azithromycin. Cardiovasc Toxicol. 2017;17:434–440. doi: 10.1007/s12012-017-9401-7
15.
Capel RA, Herring N, Kalla M, Yavari A, Mirams GR, Douglas G, Bub G, Channon K, Paterson DJ, Terrar DA, et al. Hydroxychloroquine reduces heart rate by modulating the hyperpolarization-activated current If: novel electrophysiological insights and therapeutic potential. Heart Rhythm. 2015;12:2186–2194. doi: 10.1016/j.hrthm.2015.05.027
16.
Kauthale RR, Dadarkar SS, Husain R, Karande VV, Gatne MM. Assessment of temperature-induced hERG channel blockade variation by drugs. J Appl Toxicol. 2015;35:799–805. doi: 10.1002/jat.3074
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Aromolaran AS, Srivastava U, Alí A, Chahine M, Lazaro D, El-Sherif N, Capecchi PL, Laghi-Pasini F, Lazzerini PE, Boutjdir M. Interleukin-6 inhibition of hERG underlies risk for acquired long QT in cardiac and systemic inflammation. PLoS One. 2018;13:e0208321. doi: 10.1371/journal.pone.0208321
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Simpson TF, Kovacs RJ, Stecker EC. Ventricular arrhythmia risk due to hydroxychloroquine-azithromycin treatment for COVID-19 [published online March 29, 2020]. Cardiology Magazine. https://www.acc.org/latest-in-cardiology/articles/2020/03/27/14/00/ventricular-arrhythmia-risk-due-to-hydroxychloroquine-azithromycin-treatment-for-covid-19
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Published online: 8 April 2020
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Dr Roden has nothing to disclose. Dr Harrington is the president of the American Heart Association (unpaid) and served on the Stanford Healthcare Board of Directors from 2016 to 2018 (unpaid). Dr Poppas is the president of the American College of Cardiology. Dr Russo is the president of the Heart Rhythm Society; receives research study support from Boehringer Ingelheim, Boston Scientific, and Medilynx (all funding to the hospital); and serves on the Research Steering Committee for Boston Scientific and the Apple Heart Study (no honoraria).
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